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    Clinical Trial Results:
    An Open-Label, Single-arm, Phase Ib/II study of AEB071 (a Protein Kinase C Inhibitor) and Everolimus (mTOR inhibitor) in Patients with CD79-mutant or ABC subtype Diffuse Large B-Cell Lymphoma

    Summary
    EudraCT number
    		 2013-001265-16
    Trial protocol
    		 IT   DE   NL   FR  
    Global end of trial date
    01 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jun 2017
    First version publication date
    08 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COEB071X2103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01854606
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ND: ND
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, 41 613241111,
    Scientific contact
    Novartis Pharmaceuticals AG, Novartis Pharmaceuticals AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The Phase Ib part of the study was to estimate the maximum tolerated dose/recommended Phase II dose (MTD/RP2D) of the combination of sotrastaurin and everolimus in patients with CD79 mutant and/or activated B-cell (ABC) subtype diffuse large B-cell lymphoma (DLBCL). The Phase II part was to assess the preliminary evidence of anti-tumor activity at the RP2D for the combination of sotrastaurin and everolimus in the same patient population (i.e. patients with a CD79 mutation and in those wild-type for the mutation but of the ABC subtype). However, due to suboptimal tolerability of the combination treatment of sotrastaurin and everolimus in the Phase Ib part of the study, the Phase II part was not initiated nor conducted.
    Protection of trial subjects
    This study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    31
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    16
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 At the study termination date (01-Jun-2016), all 31 patients had discontinued study.

    Pre-assignment
    Screening details
    		 A minimum of 70 patients (at least 15 for Phase Ib and approximately 55 for Phase II) were to be enrolled. At the time of enrollment halt, a total of 31 patients were enrolled into the Phase Ib part of the study. Treatment arms were described by sotrastaurin dose and regimen only since the dose and regimen of everolimus remained constant.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 200mg Sotrastaurin + 2.5 mg everolimus
    Arm description
    		 Sotrastaurin 200 mg twice daily + everolimus 2.5 mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AEB071
    Investigational medicinal product code
    Other name
    Sotrastaurin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive sotrastaurin orally, twice a day (at approximately 12-hour intervals). The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive 2.5mg everolimus once daily. The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Arm title
    		 250mg Sotrastaurin + 2.5 mg everolimus
    Arm description
    		 Sotrastaurin 250 mg twice daily + everolimus 2.5 mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AEB071
    Investigational medicinal product code
    Other name
    Sotrastaurin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive sotrastaurin orally, twice a day (at approximately 12-hour intervals). The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive everolimus once daily. The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Arm title
    		 300mg Sotrastaurin + 2.5 mg everolimus
    Arm description
    		 Sotrastaurin 300 mg twice daily + everolimus 2.5 mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AEB071
    Investigational medicinal product code
    Other name
    Sotrastaurin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive sotrastaurin orally, twice a day (at approximately 12-hour intervals). The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive everolimus once daily. The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Arm title
    		 400mg Sotrastaurin + 2.5 mg everolimus
    Arm description
    		 Sotrastaurin 400 mg twice daily + everolimus 2.5 mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    AEB071
    Investigational medicinal product code
    Other name
    Sotrastaurin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive sotrastaurin orally, twice a day (at approximately 12-hour intervals). The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    RAD001
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were to receive everolimus once daily. The patient’s dose of each study drug depended upon which dose level the patient was assigned to. Patients were dosed on a flat, fixed dose and not by body weight or body surface area.

    Number of subjects in period 1
    		200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Started
    3
    16
    6
    6
    Completed
    0
    0
    0
    0
    Not completed
    3
    16
    6
    6
         Adverse event, serious fatal
    -
    4
    1
    2
         Consent withdrawn by subject
    1
    1
    2
    2
         Physician decision
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    3
    -
    -
         Follow-up phase completed as per protocol
    2
    7
    2
    2
         Lost to follow-up
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    200mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 200 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    250mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 250 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    300mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 300 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    400mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 400 mg twice daily + everolimus 2.5 mg once daily

    Reporting group values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus Total
    Number of subjects
    		 3 16 6 6 31
    Age categorical
    Units: Subjects
        < 65 Years
    		 2 6 3 5 16
        65 to < 85 Years
    		 1 10 3 1 15
    Age continuous
    Full Analysis Set (FAS): Consisted of all patients who received at least one full or partial dose of sotrastaurin or everolimus. Patient data were analyzed according to the planned treatment combination. Unless otherwise specified, FAS is the default set for Phase Ib data analysis.
    Units: years
        arithmetic mean (standard deviation)
    		 58 ± 7 64.8 ± 10.62 59.2 ± 14.06 55.5 ± 13.52 -
    Gender categorical
    Units: Subjects
        Female
    		 1 4 0 3 8
        Male
    		 2 12 6 3 23

    End points

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    End points reporting groups
    Reporting group title
    200mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 200 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    250mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 250 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    300mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 300 mg twice daily + everolimus 2.5 mg once daily

    Reporting group title
    400mg Sotrastaurin + 2.5 mg everolimus
    Reporting group description
    		 Sotrastaurin 400 mg twice daily + everolimus 2.5 mg once daily

    Subject analysis set title
    0-0.16
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose determining set (DDS): The DDS consisted of all patients from the Safety Set who either met the minimum exposure criterion and had sufficient safety evaluations during Cycle 1, or experienced a DLT during Cycle 1. A patient was considered to have met the minimum exposure criterion if they received at least 21 out of the 28 planned daily combination doses of sotrastaurin (bid) and everolimus (qd) in the first 28 days of dosing. Patients who did not experience a DLT during the first cycle were considered to have sufficient safety evaluations if they were observed for at least 28 days following the first dose and were considered by both Novartis and Investigators to have had enough safety data to conclude that a DLT did not occur.

    Subject analysis set title
    0.16-0.35
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose determining set (DDS).

    Subject analysis set title
    0.35-1
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Dose determining set (DDS).

    Subject analysis set title
    All Dose Cohorts
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS): Consisted of all patients who received at least one full or partial dose of sotrastaurin or everolimus. Patient data were analyzed according to the planned treatment combination. Unless otherwise specified, FAS is the default set for Phase Ib data analysis.

    Primary: Posterior Distribution of Dose Limiting Toxicities (DLTs) rates at time of last dose escaltion meeting, 2.5 mg Everolimus

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    End point title
    		 Posterior Distribution of Dose Limiting Toxicities (DLTs) rates at time of last dose escaltion meeting, 2.5 mg Everolimus [1]
    End point description
    Dose determining set (DDS): The DDS consisted of all patients from the Safety Set who either met the minimum exposure criterion and had sufficient safety evaluations during Cycle 1, or experienced a DLT during Cycle 1. A patient was considered to have met the minimum exposure criterion if they received at least 21 out of the 28 planned daily combination doses of sotrastaurin (bid) and everolimus (qd) in the first 28 days of dosing. Patients who did not experience a DLT during the first cycle were considered to have sufficient safety evaluations if they were observed for at least 28 days following the first dose and were considered by both Novartis and Investigators to have had enough safety data to conclude that a DLT did not occur.
    End point type
    Primary
    End point timeframe
    Approximately 12 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses.
    End point values
    		 0-0.16 0.16-0.35 0.35-1
    Number of subjects analysed
    28 [2]
    28 [3]
    28 [4]
    Units: probability
    number (not applicable)
        250mg sotrastaurin
    0.37
    0.616
    0.014
        300mg sotrastaurin
    0.231
    0.738
    0.031
        350mg sotrastaurin
    0.137
    0.783
    0.08
        400mg sotrastaurin
    0.086
    0.743
    0.171
        450mg sotrastaurin
    0.061
    0.66
    0.279
    Notes
    [2] - all patients in DDS
    [3] - all patients in DDS
    [4] - all patients in DDS
    No statistical analyses for this end point

    Primary: Posterior Distribution of Dose Limiting Toxicities (DLTs) Rates at time of last dose escation meeting, 5.0 mg Everilimus

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    End point title
    		 Posterior Distribution of Dose Limiting Toxicities (DLTs) Rates at time of last dose escation meeting, 5.0 mg Everilimus [5]
    End point description
    Analysis done in the Dose determining set (DDS).
    End point type
    Primary
    End point timeframe
    Approximately 12 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses.
    End point values
    		 0-0.16 0.16-0.35 0.35-1
    Number of subjects analysed
    28 [6]
    28 [7]
    28 [8]
    Units: Probability
    number (not applicable)
        250mg sotrastaurin
    0.155
    0.682
    0.162
        300mg sotrastaurin
    0.098
    0.602
    0.3
        350mg sotrastaurin
    0.069
    0.488
    0.443
    Notes
    [6] - All patients in the DDS
    [7] - All patients in the DDS
    [8] - All patients in the DDS
    No statistical analyses for this end point

    Primary: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1

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    End point title
    		 Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 [9]
    End point description
    Estimate the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the AEB071and EVEROLIMUS combination therapy in patients with DLBCL in the Dose determining set (DDS). A patient with multiple occurrences of DLTs under one treatment is counted only once in the AE category for that treatment. A patient with multiple DLTs within a primary system organ class is counted only once in the total row.
    End point type
    Primary
    End point timeframe
    Approximately 12 months
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses.
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    14
    5
    6
    Units: Participants
        Blood and lymphatic system disorders
    0
    1
    0
    0
        -Thrombocytopenia
    0
    1
    0
    0
        Gastrointestinal disorders
    1
    0
    0
    2
        -Nausea
    0
    0
    0
    2
        -Vomiting
    0
    0
    0
    2
        -Diarrhoea
    0
    0
    0
    1
        -Stomatitis
    1
    0
    0
    0
        Infections and infestations
    0
    1
    0
    0
        -Pneumocystis jirovecii pneumonia
    0
    1
    0
    0
        Metabolism and nutrition disorders
    0
    1
    1
    0
        -Decreased appetite
    0
    0
    1
    0
        -Hypertriglyceridaemia
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Best Overall Radiological Response

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    End point title
    		 Best Overall Radiological Response
    End point description
    Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS in the Dose determining set (DDS).
    End point type
    Secondary
    End point timeframe
    approximately 24 months
    End point values
    		 All Dose Cohorts
    Number of subjects analysed
    31
    Units: Patients
        Complete response
    1
        Partial response
    4
        Stable disease
    9
        Progressive disease
    6
        Unknown best overall response
    11
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Area Under Curve

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    End point title
    		 Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Area Under Curve
    End point description
    Pharmacokinetic Analysis Set: Consisted of all patients who had evaluable PK data. The Pharmacokinetic Analysis Set was used for summaries (tables and figures) and listings of derived PK data. Patients could be removed from the estimation of certain PK parameters on an individual basis depending on the number of available blood samples. These patients were identified at the time of the analyses. Area Under Curve (AUC0-8h) = Area under the concentration-time curve from time 0 to 8 hours post-dose [mass x time x volume-1]
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: hr*ng/mL
    median (full range (min-max))
        Day 1
    7660 (7660 to 7660)
    14000 (3960 to 35800)
    18600 (14100 to 23900)
    29000 (27700 to 30300)
        Day 15
    13200 (11500 to 17400)
    19100 (8590 to 37200)
    30100 (23400 to 81900)
    36800 (14100 to 51700)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Cmax

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    End point title
    		 Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Cmax
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Cmax=Maximum observed concentration after drug administration [mass x volume-1].
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: ng/ml
    median (full range (min-max))
        Day 1
    3420 (3420 to 3420)
    2970 (718 to 5780)
    3310 (2500 to 3640)
    7690 (7370 to 8000)
        Day 15
    2530 (2320 to 2870)
    3840 (1770 to 6280)
    4610 (3470 to 12900)
    5270 (3700 to 9870)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Tmax

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    End point title
    		 Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Tmax
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Tmax=Time to reach Cmax [time]
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: hr
    median (full range (min-max))
        Day 1
    1 (1 to 1)
    2 (0.5 to 5.98)
    3.97 (0.967 to 4.17)
    0.992 (0.983 to 1)
        Day 15
    1.08 (1 to 1.93)
    2 (0.5 to 4.05)
    4.05 (2 to 4.25)
    1 (0.533 to 2.05)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Racc

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    End point title
    		 Primary PK Parameters for Whole Blood Sotrastaurin by Treatment Group - Racc
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Racc = Accumulation ratio calculated as AUC0-8h or AUCtau at Day 15/AUC0-8h or AUCtau at Day 1
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: Ratio
    median (full range (min-max))
        Day 15
    1.51 (1.51 to 1.51)
    1.41 (1.04 to 4.7)
    1.26 (1.26 to 1.26)
    1.11 (0.51 to 1.71)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Everolimus by Treatment Group - Area Under Curve

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    End point title
    		 Primary PK Parameters for Whole Blood Everolimus by Treatment Group - Area Under Curve
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Area Under Curve (AUC0-8h) = Area under the concentration-time curve from time 0 to 8 hours post-dose [mass x time x volume-1]
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: hr*ng/mL
    median (full range (min-max))
        Day 1
    40.7 (40.7 to 40.7)
    62.6 (51 to 152)
    57.1 (41 to 145)
    58.9 (26.1 to 132)
        Day 15
    98 (78 to 140)
    115 (56.6 to 181)
    221 (185 to 238)
    161 (149 to 161)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Cmax

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    End point title
    		 Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Cmax
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Cmax=Maximum observed concentration after drug administration [mass x volume-1].
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: ng/ml
    median (full range (min-max))
        Day 1
    7.62 (7.62 to 7.62)
    12.5 (7.78 to 31.9)
    11.4 (7.36 to 40.6)
    11 (4.57 to 34.6)
        Day 15
    18.7 (12.8 to 23.6)
    17.5 (13.7 to 37.6)
    32.5 (29 to 40.9)
    27.9 (23.5 to 30.9)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Tmax

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    End point title
    		 Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Tmax
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Tmax = Time to reach Cmax [time]
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: hr
    median (full range (min-max))
        Day 1
    4 (4 to 4)
    1.54 (0.5 to 6)
    2.48 (0.967 to 4.17)
    2 (0.967 to 6)
        Day 15
    1.93 (1.08 to 3.98)
    2 (0 to 4.05)
    1.64 (1.64 to 1.64)
    2.08 (1.22 to 5.7)
    No statistical analyses for this end point

    Secondary: Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Racc

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    End point title
    		 Primary PK Parameters for Whole Blood Everolimus by Treatment Group – Racc
    End point description
    Analysis done in the Pharmacokinetic Analysis Set. Racc = Accumulation ratio calculated as AUC0-8h or AUCtau at Day 15/AUC0-8h or AUCtau at Day 1
    End point type
    Secondary
    End point timeframe
    Approximately 24 months (Day 1 and Day 15 of Cycle 1)
    End point values
    		 200mg Sotrastaurin + 2.5 mg everolimus 250mg Sotrastaurin + 2.5 mg everolimus 300mg Sotrastaurin + 2.5 mg everolimus 400mg Sotrastaurin + 2.5 mg everolimus
    Number of subjects analysed
    3
    16
    6
    6
    Units: Ratio
    median (full range (min-max))
        Day 15
    2.41 (2.41 to 2.41)
    1.37 (1.19 to 2.62)
    1.64 (1.64 to 1.64)
    2.08 (1.22 to 5.07)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    AEB 200 mg bid +@ RAD 2.5 mg qd
    Reporting group description
    		 AEB 200 mg bid +@ RAD 2.5 mg qd

    Reporting group title
    AEB 250 mg bid +@ RAD 2.5 mg qd
    Reporting group description
    		 AEB 250 mg bid +@ RAD 2.5 mg qd

    Reporting group title
    AEB 300 mg bid +@ RAD 2.5 mg qd
    Reporting group description
    		 AEB 300 mg bid +@ RAD 2.5 mg qd

    Reporting group title
    AEB 400 mg bid +@ RAD 2.5 mg qd
    Reporting group description
    		 AEB 400 mg bid +@ RAD 2.5 mg qd

    Reporting group title
    All@patients
    Reporting group description
    		 All@patients

    Serious adverse events
    		 AEB 200 mg bid +@ RAD 2.5 mg qd AEB 250 mg bid +@ RAD 2.5 mg qd AEB 300 mg bid +@ RAD 2.5 mg qd AEB 400 mg bid +@ RAD 2.5 mg qd All@patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    11 / 16 (68.75%)
    3 / 6 (50.00%)
    5 / 6 (83.33%)
    20 / 31 (64.52%)
         number of deaths (all causes)
    0
    4
    1
    2
    7
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Intracardiac mass
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    4 / 31 (12.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 31 (12.90%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Citrobacter infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 31 (9.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AEB 200 mg bid +@ RAD 2.5 mg qd AEB 250 mg bid +@ RAD 2.5 mg qd AEB 300 mg bid +@ RAD 2.5 mg qd AEB 400 mg bid +@ RAD 2.5 mg qd All@patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    15 / 16 (93.75%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    30 / 31 (96.77%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Superior vena cava occlusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    General disorders and administration site conditions
    Catheter site swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Face oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 16 (12.50%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    9 / 31 (29.03%)
         occurrences all number
    1
    2
    3
    4
    10
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    0
    1
    2
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    3
    2
    0
    5
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    6 / 31 (19.35%)
         occurrences all number
    2
    2
    0
    2
    6
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    5 / 31 (16.13%)
         occurrences all number
    0
    3
    1
    1
    5
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    0
    0
    2
    Lung infiltration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    1
    1
    3
    Oropharyngeal plaque
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    1
    0
    0
    2
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    1
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    4 / 31 (12.90%)
         occurrences all number
    0
    0
    1
    4
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    5 / 31 (16.13%)
         occurrences all number
    0
    1
    2
    2
    5
    Biopsy skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    0
    2
    Blood cholesterol abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    2
    0
    0
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    1
    0
    2
    Neutrophil count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    0
    5
    6
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    0
    2
    Urine output decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    0
    2
    3
    Dysgeusia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    0
    1
    2
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 16 (37.50%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    10 / 31 (32.26%)
         occurrences all number
    1
    8
    3
    1
    13
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    3
    0
    0
    3
    Lymph node pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 16 (18.75%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    7 / 31 (22.58%)
         occurrences all number
    1
    3
    7
    3
    14
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 16 (43.75%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    10 / 31 (32.26%)
         occurrences all number
    1
    15
    7
    4
    27
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Eye disorders
    Eyelids pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    1
    0
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    1
    0
    2
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 16 (31.25%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    10 / 31 (32.26%)
         occurrences all number
    1
    6
    5
    2
    14
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    12 / 31 (38.71%)
         occurrences all number
    0
    3
    9
    10
    22
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Duodenal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    3
    0
    4
    Epigastric discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Impaired gastric emptying
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Melaena
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    9 / 16 (56.25%)
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    21 / 31 (67.74%)
         occurrences all number
    2
    9
    7
    11
    29
    Stomatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 16 (18.75%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    8 / 31 (25.81%)
         occurrences all number
    1
    3
    1
    4
    9
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 16 (37.50%)
    3 / 6 (50.00%)
    6 / 6 (100.00%)
    15 / 31 (48.39%)
         occurrences all number
    0
    8
    6
    9
    23
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    1
    1
    3
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 31 (12.90%)
         occurrences all number
    0
    5
    0
    1
    6
    Rash maculo-papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    1
    1
    2
    Rash papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin texture abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Chromaturia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    0
    1
    3
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Enuresis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    0
    0
    2
    Oliguria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Ureteric obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    3 / 31 (9.68%)
         occurrences all number
    0
    1
    1
    1
    3
    Flank pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    2
    0
    2
    Pain in jaw
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    0
    0
    0
    1
    Candida infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Herpes simplex
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Rash pustular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 16 (37.50%)
    4 / 6 (66.67%)
    4 / 6 (66.67%)
    15 / 31 (48.39%)
         occurrences all number
    1
    7
    4
    6
    18
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    2
    2
    Fluid imbalance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    1
    0
    1
    Fluid retention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    4
    1
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    1
    0
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    2
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    6 / 31 (19.35%)
         occurrences all number
    0
    5
    1
    2
    8
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    4 / 31 (12.90%)
         occurrences all number
    0
    1
    2
    1
    4
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    0
    2
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 31 (3.23%)
         occurrences all number
    0
    0
    0
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2013
    •Removal of the prior anthracycline treatment criterion for inclusion of patients into the study due to differences in global standard of care in elderly DLBCL patient populations. •Correction of typographical error of exclusion criterion for abnormal laboratory values (absolute neutrophil and platelet counts). •Removal of exclusion criterion of patients with significant coagulopathy or requiring long-term systemic anticoagulation since newly obtained tumor samples was not required per protocol.
    24 Sep 2014
    •As requested by Health Authorities and to align with the everolimus IB, amend protocol exclusion criterion #12 to exclude sexually active male patients unless a condom was used during intercourse while taking study treatment and for 8 weeks after discontinuation of study treatment. •As requested by Health Authorities, include a statement that caution is necessary when administering medications which are substrates of transportation MDR1 (P-gp) and OATP1B1 because sotrastaurin may act as an inhibitor of these transporters. •Modify exclusion criterion #15 to exclude patients who received ibritumomab tiuxetan (Zevalin®) and/or tositumomab (Bexxar®) treatment less than 3 months prior to starting study drug. After 3 months of discontinuing ibritumomab or tositumomab it was expected that any bone marrow suppressive effects would have resolved. This wash-out period allowed for additional patients to be considered for the study. •Clarification of the molecular pre-screening analysis to be performed at a central Novartis-designated laboratory during the Phase Ib escalation phase and the Phase II parts of this study have been included, so it is clear to Investigators. •Allow for a CT/MRI scan that was performed prior to obtaining study informed consent, but performed per standard of care within 28 days of Cycle 1 Day 1 to be used for Screening to avoid an unnecessary repeat of this procedure. In addition, to include an EOT CT/MRI if a CT/MRI was not acquired within 6 weeks prior to the EOT visit date. This was to ensure final radiological response assessment of disease prior to patients coming off study. •Specify the required inclusion criterion for definition of measurable disease to ensure the correct radiological assessment as per non-Hodgkin’s Lymphoma International Working Group criteria. •This study only required radiological response assessment, references to additional response criteria that are not applicable for this study were removed.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial did not progress into Phase II due to the suboptimal tolerability of the combination treatment of sotrastaurin and everolimus in the Phase Ib part of the study. There were no serious safety concerns associated with this combination.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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